Composition and method for treatment of otitis media

ABSTRACT

The present invention discloses a method of increasing and enhancing mammalian eustachian tube lumen patency and pressure equalization performance by administering an aerosolized mixture of lipid crystals comprised of a mixture of one or more lipids surfactants and one or more spreading agents selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, in powder form, and one or more fluorocarbon propellants through a mammalian nasal orifice. Upon administration, the propellant(s) are evaporated from the mixture and the lipid crystals are deposited at a subject mammalian eustachian tube whereupon said lipid crystals come into contact with lumen surfaces of the tube forming an amorphous spread film thereupon substantially decreasing the opening pressure of the lumen. In a second preferred embodiment, a therapeutically active agent effective in the treatment of otitis media is added to the mixture of lipid crystals and upon administration of said aerosol mixture, the amorphous spread film formed thereby carries said therapeutically active agent through the eustachian tube to the tissues of the middle ear.

This is a continuation of U.S. patent application Ser. No. 09/450,884now U.S. Pat. No. 6,156,294 filed on Nov. 28, 1999.

FIELD OF INVENTION

The present invention relates to the field of pharmacologicalcompositions and methods of utilizing such compositions in order toimprove the flow of both naturally occurring fluids and pharmacologicagents through the mammalian eustachian tube.

BACKGROUND OF THE INVENTION

Otitis media is a pathological condition common to mammalian species,and most common to children. During episodes of otitis media, fluidaccumulates in the middle ear or, as it is also known, the tympaniccavity.

Acute otitis media is a condition in which fluid accumulation in themiddle ear is accompanied by signs or symptoms of ear infection(including both viral and if bacterial etiologies). Such pathology mayexhibit a bulging eardrum accompanied by pain or, in some instances,perforation of the tympanic membrane. Such perforations may also beaccompanied by drainage of purulent material. In contrast, otitis mediawith effusion is typified by fluid accumulation within the tympaniccavity without signs of infection.

Both acute otitis media and otitis media with effusion may causesubstantial pain as pressure increases, positively or negatively, withinthe confines of the tympanic chamber. Antibiotics, steroids, andantibiotics in combination with steroids have been utilized to treatotitis media. Antihistamine/decongestants have also been utilized in thetreatment of otitis media with effusion.

The anatomical features of the middle ear define what can be describedas a sealed chamber. On its lateral border, the middle ear iseffectively isolated from the external auditory meatus (in the absenceof a punctured ear drum), by the tympanic membrane. Medially, the middleear is effectively sealed from the inner ear by a bony wall. Theposterior wall of the tympanic cavity communicates with a large, buteffectively sealed mastoid antrum. Only the anterior wall of the middleear contains a passageway for effective communication outside of thetympanic cavity. There, a natural pathway provided by the auditory or,as it is also known, the eustachian tube, provides communication withthe nasopharynx.

As stated above, during episodes of acute otitis media, the painfulincreased middle ear pressure may naturally resolve through a resultantperforation of, and drainage through, the tympanic membrane. However,the increased fluid pressure associated with otitis media with effusiondoes not resolve via this mechanism. In fact, for those patientssuffering otitis media for prolonged periods of time, and especially forthose evidencing significant associated hearing loss, myringotomy withthe placement of a tympanostomy tube may be indicated as a means ofequalizing middle ear pressure and in order to restore normal hearing.Recently, laser surgery has also been utilized to provide an aperturethrough the tympanic membrane through which the fluid trapped within themiddle ear may drain. Besides the perforations of the eardrum providedby infection (acute otitis media), myringotomy and laser surgery, theeustachian tube, a natural middle ear drainage path described above, isprovided by mammalian anatomy. Unfortunately, during episodes of otitismedia with effusion (OME), a time when the natural pathway and pressurerelief functions of the eustachian tube would be most useful, theincrease pressure required to open the lumen (as described in moredetail above and below), effectively eliminates this means of relievingmiddle ear pressurization. Reduced patency of the eustachian tube isbelieved to be one of the primary causes of OME in pediatric patients.In fact, it is known that OME elevates eustachian tube opening pressureindependent of other pathological conditions effecting this conduit. Theterm “opening pressure” as it is utilized throughout this disclosure andwithin the claims, refers to the pressure, typically measured inmillimeters of mercury, necessary to cause the lumen of the auditorytube to open and provide a patent pathway between the nasopharynx andtympanic cavity.

Treatment of otitis media by means of administration ofanti-inflammatory agents, antibiotics, decongestants and/oranti-histamines, or combinations thereof, is limited in effectivenessas, in the absence of perforation, there is presently no method fordirect application of such drugs directly to target tissues of theeustachian tube and/or middle ear. Systemic applications of drugs viaparenteral or oral routes, while eventually reaching the eustachian tubeand middle ear, may have adverse systemic effects and, more importantly,are not especially effective at delivering a concentrated dose of theapplicable drugs where they are truly needed, directly to the targettissues. Simply put, the sealed chamber anatomy of the middle ear has,up until the present time, constituted a barrier to direct drugapplication.

Although the central lumen of the eustachian tube does provide a pathwayto the tympanic cavity, it is, as described below, ordinarily closed andresistant to fluid passage due to its inherent anatomical configuration.During episodes of otitis media, the relatively high surface tensionspresent at the air/liquid interface located upon the epithelial liningof the tube lumen further increase the opening pressure required to openthis channel. Although direct application of therapeutically activeagents, effective in the treatment of otitis media, to the lumen of theeustachian tube, and via the lumen to the middle ear, would be highlyadvantageous in treating otitis media, no method or composition has yetbeen disclosed capable of overcoming the surface tension within the tubelumen so as to facilitate opening of the tube and transport of suchdrugs throughout the lumen and on to the tissues of the middle ear. Whatis needed is a composition and method of applying same, especiallyformulated and adapted to decrease the surface tension of the auditorytube so as to decrease the opening pressure thereof thereby providing apatent conduit for therapeutic agents, effective in the treatment ofotitis media, to travel through said tube to effectively treat saidcondition.

Pathological conditions can arise from, and can cause changes in surfacetension values of air/liquid interfaces in other organs of mammaliananatomy. The naturally occurring “surfactant system” secreted upon theepithelial lining of the lung which is deficient in cases of R.D.S. isknown to be comprised of a complex mixture of lipids, proteins andcarbohydrates (as described in a recent review: Surfactants and theLining of the Lung, The John Hopkinds University Press, Baltimore,1988). The prime function of the surfactant system is to stabilize thealveoli and associated small airways against collapse by decreasing thesurface tension at the air/liquid interface. It is now believed that theaction of the phospholipid component of the surfactant system is theprincipal source of the powerful surface tension reduction effect of thenaturally occurring surfactant system of the lung. More specifically, itis known that the fully saturated diacylphospholipids, principally,dipalmitoyl phosphatidylcholine (DPPC) provide liquid balance andanti-collapse properties to the lung's epithelial lining. In addition toDPPC, spreading agents, also found within the naturally occurringsurfactant system, assist DPPC in rapidly forming a uniform spread filmon the air/liquid surfaces of the lung. Such spreading agents includecholesteryl esters such as, for example, cholesteryl palmitate (CP);phospholipids such as, for example, diacylophosphatidylglycerols (PG),diacylphosphatidylethanolamines (PE), diacylphosphatidylserines (PS),diacylphosphatidylinositols (PI), sphingomelin (Sph) and Cardiolipin(Card); and virtually and other phospholipid, and of thelysophospholipids; or any of the plasmalogens, dialklylphospholipids,phosphonolipids, carbohydrates and proteins, such as, for example,albumin, pulmonary surfactant proteins A, B, C and D. The naturallyoccurring surfactant system is further described in U.S. Pat. No.5,306,483.

DPPC has been administered to infants with respiratory distress syndromeas a therapeutic measure. For this purpose, DPPC has been administeredby means of an aqueous aerosol generator (utilized with an incubator inwhich the infant resided during treatment). Endotracheal administrationhas also been utilized. DPPC therapy has been typified as utilizingnatural surfactants (harvested from porcine or bovine lungs), orartificial, commercially synthesized compounds.

It has also heretofore been disclosed to utilize therapeutic agents, incombination with surfactant/spreading agents to effectively administerdrug therapy uniformly throughout the epithelial lining of the lung.U.S. Pat. No. 5,306,483 (the “'483 patent”) discloses a process toprepare lipid crystalline figures in fluorocarbon propellants for thedelivery of therapeutically active substances which form amorphousfluids on delivery at the air/liquid interface of the lung and which canbe utilized as an effective drug delivery system. More specifically,said patent discloses a process comprising (a) preparing a mixture ofone or more lipids of the group of phospholipids known asphosphatidylcholines and one or more spreading agents, in powder formand a therapeutically active substance and one or more fluorocarbonpropellants, said lipids, spreading agents and therapeutically activesubstances being insoluble in the propellants; and (b) evaporating thepropellants from the mixture. The '483 patent teaches the combination ofdipalmitoyl phosphatidylcholine (DPPC) or any of the other fullysaturated Acyl chain phospholipids, 80.0 to 99.5% by weight, and otherspreading agents, for example, phospholipids such as, but not limited toPG, PE, PS, PI, lysophospholipids, plasmalogens, dialkylphospholipids,diether phosphonolipids, Cardiolipin, sphingomyelin, 0.5 to 20.0%weight, neutral lipids like cholesteryl esters such as, but no limitedto, cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate, 0.5to 10% by weight, carbohydrates, such as, but not limited to, glucose,fructose, galactose, pneumogalactan, dextrose, 0.5 to 10% by weight, andproteins such as, but not limited to albumin, pulmonary surfactantspecific proteins A, B, C, and D 0.5 to 10% by weight, compounds inlipid-crystalline structures in fluorocarbon (both chloro- andhydrofluorocarbon) propellants in which therapeutically active agents,drugs and other materials can be carried into the lungs after releasefrom and through metered dose nebulizer. The spreading agents referredto in the '483 patent are compounds such as the above-describedphospholipids, lysophospholipids, plasmalogens, dialklyphospholipids,phosphonolipids, carbohydrates and proteins. The function of thespreading agent is to assist DPPC, or other phospholipids such as, forexample, DPPG, in rapidly adsorbing and forming a spread film upon theair/liquid surfaces of the lungs. In addition, the '483 patent alsodiscloses a process for preparing such lipid crystalline figures influorocarbon propellants without a therapeutically active substance foruse as a tear (as for the eye).

Although the '483 patent does disclose a process for preparing a drugdelivery system especially adapted for uniformly applying a therapeuticagent to the epithelial lining of the lung, heretofore, no method orcomposition has been disclosed in the past that is particularly adapted,configured and formulated for the delivery of therapeutic agents totarget tissues of the eustachian tube, or, via the eustachian tube, themiddle ear.

Otitis media can, due to fluid accumulation, cause significant pressure,both positive and negative, in the afore-mentioned confines of themiddle ear. Pressure differentials between the middle ear and thesurrounding atmosphere, whether due to the addition of such fluids, ordue to the relative decrease or increases of ambient atmosphericpressure, can cause great pain and discomfort. Such pressure conditionssubject the tympanic membrane, and the associated pain receptors, tobulging and stretching. In addition, the accumulation of fluids, and theresulting static tension applied to the tympanic membrane, can greatlyreduce hearing.

As mentioned above, the eustachian tube is specifically adapted toprovide communication between the middle ear (a sealed chamber), andambient atmospheric pressure, by providing a pathway between thetympanic cavity and the nasopharynx. Thus the auditory tube serves as apressure equalization means for the middle ear. However, in order toprovide this equalization function, and, at the same time, allow propermiddle ear sound conduction, the eustachian tube, and the pathway itprovides between the middle ear and the nasopharynx, are ordinarilyclosed. The lumen of the tube, as discussed below, is ordinarily openonly during the act of swallowing and other movements that causecontraction of the attached musculature.

In humans, the eustachian tube is, on the average, 3.5 cm in length. Theposterior one third of the tube is comprised of a bony wall with theanterior two thirds of the tubular structure being cartilaginous incomposition. The auditory tube provides, by means of a central lumen, afluid passage way between the nasopharynx and middle ear. However, thesomewhat flattened medial and lateral walls of the tube are ordinarilyin direct contact occluding and effectively limiting passage of liquidsand gasses therethrough and allowing optimal sound conduction functionof the middle ear which requires a sealed chamber. During swallowing,the tensor veli palatini muscle, which inserts into the lateral surfaceof the cartilaginous portion of the tube, contracts and pulls the wallof the tube laterally opening the central lumen thereby providing thecommunicating pathway needed for fluid flow between the middle ear andthe nasopharynx. The action of the muscle upon the tube is needed toovercome the surface tension attracting the flattened medial and lateralwalls of the central lumen together as well as the elastic recoil of thetube cartilage which also tends to close the lumen. The surface tensionis due to the sero-mucous secretions found on the epithelial lining ofthe lumen.

In normal physiologic function, the sero-mucous secretions of theauditory tube, and the relatively low surface tensions they produce atthe lateral and medial walls of the lumen, do not interfere with thenormal opening and related pressure equalization functions of theauditory tube. However, middle ear, tube and upper respiratoryinfections and/or inflammatory conditions, such as allergies, cangreatly effect the nature and increase the amount of the secretionsfound upon the lumen surface. Generally, such pathologic conditionsgreatly increase the surface tension of the lumen walls by increasingthe relative amount of mucoid secretions, effectively interfering with,or completely preventing the opening of the tube. In addition, thetissues of the eustachian tube may become inflamed and engorged withfluids and cause further increases in opening pressures.

The above-described alterations in the nature and amount of secretionsas well as inflammation of tube tissues are common during episodes ofotitis media. Therefore, at a time when eustachian tube drainage of themiddle ear would be highly desirable, this normally effectivephysiologic means of eliminating painful pressure often associated withsuch pathology is either hindered or completely eliminated. The commoncold, flu, hay fever and other allergies can also result in eustachiantube failure for the same reason. However, inflammatory changes in tubetissues and lumen secretions are not the exclusive cause of suchauditory tube failures.

Rapid changes in ambient pressure may also inhibit or completely preventnormal equalization functions of the auditory tube. If ambient pressurechanges too quickly, the pressure gradient between the atmosphere andtympanic cavity may be too great to allow lumen opening. For example,the pressure within the tympanic cavity of a diver who, for example,ascends from a relatively deep dive without effectively and continuouslyequilibrating his or her middle ear through action of the eustachiantube (by swallowing, wiggling the jaw or utilizing other means tocontract the attached musculature) can experience terrific pain know asa “squeeze” which may be very difficult to overcome. Such situations aremore likely in such instances when, for example, a diver engages in suchactivity, wisely or unwisely, while he is or she is suffering from anallergy or cold (for the above-described reasons). By rising in depthwithout frequent and effective eustachian tube function, the relativelylow ambient pressure surrounding the diver effectively seals off theeustachian tubes communication with the relatively highly pressurizedmiddle ear. A diver, under such circumstances, may simply descend back afew feet to a depth where the pressure gradient is non-existent orminimal, and thereby lower the opening pressure of the auditory tubeallowing it to open and equalize the tympanic cavity. However, apassenger on a plane is in no position to change altitudes to obtain a“second chance” to equilibrate. If such a passenger is unable tofrequently and effectively equilibrate the middle ear during altitudechanges due to, for example, increased secretions within the tuberesulting from a cold, he or she is forced to bear significant pain.

Although, as described below, surfactant compositions, both natural andartificial, have been heretofore known, formulated and utilized todecrease surface tension within the lung, no such compositions, ormethods for administering said compositions, have been heretoforesuggested, taught or disclosed in regards to decreasing the surfacetension within the lumen of the eustachian tube. Likewise, no method hasheretofore been known which provides an effective decrease in openingresistance of the eustachian tube while simultaneously enhancing thepressure equilibration functions thereof.

SUMMARY OF THE INVENTION

Now, in accordance with the present invention, a method of increasingand enhancing mammalian eustachian tube lumen patency and pressureequalization performance is disclosed.

In a first preferred embodiment of the present invention, a mixture ofone or more lipids and one or more spreading agents selected from thegroup consisting of cholesteryl esters, phospholipids, carbohydrates,and proteins, all in powder form, and one or more fluorocarbonpropellants is prepared. The lipids and the spreading agents areadvantageously selected to be insoluble in the propellants. The lipidsutilized in practicing the method of the present invention are presentin an amount of about 80 to 99.5 percent by weight and the spreadingagents are present in an amount of about 0.5 to about 20 percent byweight, both based upon the total weight of the mixture. Combination ofthe one or more lipids, one or more spreading agents and one or morefluorocarbon propellants results in the formation of lipid crystals anddescribed in more detail, below. A metered dose of the mixture of lipidcrystals is then administered, via an external nasal orifice into amammal upon which the present method is practiced.

Upon administration, the propellant(s) are evaporated from the mixtureand the lipid crystals are deposited at a nasopharyngeal, or as it mayalso be described, an anterior terminus, of a subject mammalianeustachian tube whereupon said lipid crystals come into contact withlumen surfaces of the tube. Upon contact with lumen surface tissue andair/liquid interfaces of the eustachian tube lumen, the mixture of lipidcrystals forms an amorphous spread film upon said air/liquid interfaceeffectively decreasing the opening pressure thereof.

The lipid crystals deposited upon the lumen surfaces and air/liquidinterface thereupon is comprised of one or more lipids which areadvantageously selected to demonstrate powerful surfactant activity. Inaddition, the spreading agent combined therewith provides complete anduniform distribution of the surfactant over and upon the lumenair/liquid surface resulting in substantial decreases in lumen openingpressure. In turn, the decrease in lumen opening pressure results ingreater patency of the eustachian tube and thereby providing a resultantincrease in fluid conduction/equalizing function of this anatomicalstructure.

Administration of the aerosolized lipid crystals through the nasalorifice also results in deposition of said crystals upon the mucosalsurfaces of the sinus passages and sinus airways. The mucosal surfacesof these airways and sinuses also demonstrates an air/liquid interfaceformed by the secretion of muco and muco-serous secretions thereupon.Upon deposition of the lipid crystals upon these mucosal surfaces, saidcrystals form a uniform and amorphous spread film and effectively reducethe surface tension thereupon. Therefore, the present invention alsocontemplates a method for reducing the surface tension of the air/liquidsurfaces resident upon mammalian sinus and sinus air way mucosalsurfaces.

In a second preferred embodiment of the present invention, a method ofadministering therapeutically active agents, effective in the treatmentof otitis media, directly to mammalian eustachian tube and middle eartarget tissues is disclosed. In the method of the second embodiment ofthe present invention, a mixture of one or more lipids, one or morespreading agents, one or more therapeutically active agent(s), effectivein the treatment of otitis media, and one or more fluorocarbonpropellants is prepared. The one or more lipids and spreading agents areadvantageously selected from the group consisting of cholesteryl esters,phospholipids, carbohydrates, and proteins, all being in powder form.The one or more lipids, spreading agents and therapeutically activeagent(s), effective in the treatment of otitis media, are alsoadvantageously selected to be insoluble in the propellants. Inpracticing the method of the second embodiment of the present invention,the lipids are present in an amount of about 80 to 99.5 percent byweight and the spreading agents are present in an amount of about 0.5 toabout 20 percent by weight, both based upon the total weight of saidmixture. The mixture resulting from the combination of lipid(s)spreading agent(s) and therapeutically active agent and propellant formslipid crystals which act as carriers for said therapeutically activeagent. A metered dose of the mixture of lipid crystals is thenadministered, via an external nasal orifice, into a mammal upon whichthe method is practiced. A suitable bottle equipped with a metered dosevalve and nasal administration adaptor is advantageously utilized forthis purpose.

Upon administration of the lipid crystal mixture, the propellants, carrythe lipid crystals in combination with therapeutically active agent(s)effective in the treatment of otitis media to the nasopharyngealterminus of the eustachian tube whereupon the propellant(s) evaporate.The lipid crystals and therapeutically active agent is then depositedupon the tissues of the eustachian tube including the epithelial linedlumen whereupon the mixture forms an amorphous spread film effectivelycarrying said therapeutically active agent effective in the treatment ofotitis media uniformly through the eustachian tube and to target tissuesof the middle ear. As stated in further detail below, thetherapeutically active agent is advantageously selected to be effectivein the treatment of otitis media. Therefore, the second preferred methodof the present invention provides a method of administeringtherapeutically active agents directly to lumen surfaces of mammalianeustachian tubes, and also, by means of said eustachian tube lumen, tomiddle ear target tissues wherein said therapeutically active agentsprovide effective treatment for otitis media while, in addition,providing the same increased eustachian tube patency and performance asthe first embodiment.

The lipid crystals deposited upon the lumen surfaces and air/liquidinterface thereof is comprised of one or more lipids which areadvantageously selected to demonstrate powerful surfactant activity andto serve as a carrier for selected therapeutic agent(s). In addition,the spreading agent deposited therewith provides complete and uniformdistribution of the surfactant and therapeutic agent(s) throughout thelumen air/liquid surface resulting in substantial decreases in lumenopening pressure. In turn, the decrease in lumen opening pressureprovides greater patency of the eustachian tube and thus a resultantincrease in fluid conduction/equalizing function of this anatomicalstructure is provided while simultaneously providing direct applicationof therapeutically active agent to target tissues of the auditory tubeand middle ear.

Administration of the aerosolized lipid crystals with therapeuticallyactive agent through the nasal orifice also results in deposition ofsaid crystals and therapeutic agent upon the mucosal surfaces of thesinus passages and sinus airways. Therefore, the present invention alsocontemplates a method for reducing the surface tension of the air/liquidsurfaces resident upon mammalian sinus and sinus air way mucosalsurfaces while simultaneously delivering therapeutically agents thereto.

The lipids utilized in practicing the method of the present inventionmay be advantageously selected to be phospholipids, neutral lipids ormixtures thereof. The phospholipids utilized may be furtheradvantageously selected to be any phospholipid of the class known asphosphatidlycholine including any fully saturated diacylphosphatidlycholine including 1,2 dipalmitoyl phosphatidylcholine(DPPC); a diacylphosphatidylglycerol; a diacylphosphatidylethanolamine;a diacylphosphatidylserine; a diacylphosphatidylinositol; sphingomyelin,Cardiolipin, lysophospholipid; a plasmalogen; a diether phosphonolipid;or a dialklyphospholipid.

The cholesteryl esters utilized in practicing the method of the presentinvention may be advantageously selected to be cholesteryl palmitate,cholesteryl oleate or cholesteryl stearate. Carbohydrates utilized inthe present invention may be advantageously selected to be glucose,fructose, galactose, pneumogalactan, or dextrose. Proteins especiallysuited and advantageously selected for use in the present inventioninclude albumin, pulmonary surfactant specific proteins A or B or C orD, their synthetic analogs, and mixtures thereof.

The fluorocarbon propellants may be advantageously selected to bechlorofluorocarbon propellants, hydrofluorocarbons or mixtures thereof.In addition, the present invention contemplates carbon dioxide as asuitable propellant. The mixture is advantageously prepared to yieldcrystalline demonstrate a particle size equal to or less than 16 micronsin diameter. The diminutive nature of the crystalline particles is, asdiscussed in detail below, highly advantageous in enabling dispersionand application of the aerosolized mixture.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this specification and claims, the phrase “therapeuticallyactive agent” includes any substance which is capable of altering abiologic, physiologic and/or immunologic function, in nature or degreeand includes those substances generally referred to pharmacologic agentsand drugs; the term “fluorocarbons” includes the class of bothchlorofluorocarbons and hydrofluorocarbons; the term lipids includes theclass of phospholipids including, but not limited to PC, PG, PE, PI andCardiolipin; and the phrase “spreading agent(s)” refer to and includesPG, PE, PS, PI, Sph., Card., lysophospholipids, plasmalogens,dialkylphospholipids, and all others in the class phospholipid as wellas cholesteryl esters (like CP), proteins and carbohydrates.

Throughout this specification and claims, the phrase “spreadingagent(s)” refers to compounds, as listed above, which assist the one ormore lipid such as, for example, DPPC, in rapidly adsorbing and formingan amorphous spread film on air/liquid interfaces such as that foundupon the epithelial lined lumen of the auditory tube. In addition, thecompounds referred to as “spreading agent(s)”, together with the one ormore lipids, are responsible for achieving and maintaining biophysicalproperties including, but not limited to, reduction of intermolecularattractive forces, surface tension, and the resultant attractive forcesgenerated thereby, that tend to cause opposed surfaces, such as thelateral and medial epithelial lined lumen walls of the auditory tube, toadhere to each other.

The major lipid component utilized in practicing a preferred embodimentof the present invention is advantageously selected to be phospholipid1,2 dipalmitoyl, phosphatidlycholine (DPPC). DPPC is the most surfaceactive of the phospholipids or any of the subclass of fully saturatedacyl chain phospholipids. That is to say that DPPC, in combination withany spreading agent(s) disclosed herein, has a maximum effect inreducing surface tension at an air/liquid interface.

Another, minor lipid component that also acts as a spreading agent forthe major component is advantageously selected to bediacylphosphatidylglycerol (PG). The number of carbon atoms in the acylchains R and R′, (see PG formula below) can vary between 8 and 22 andmay or may not be fully saturated. DPPC and PG can be synthesized.However, since DPPC and PG are the main phospholipid constituents ofcells, they are also readily extractable from such cells by non-polarsolvents, i.e., chloroform, ether, acetone. DPPC's structural formulais:

and PG's structural formula is:

Phospholipids such as DPPC and CP may be obtained commercially, in ahighly purified form from Fluka Chemical Co. of Ronkonkoma, N.Y.; SigmaChemical CO. of St. Louis Mo.; and Avanti Polar Lipids of Birmingham,Ala. and Primedica of Cambridge, Mass.

DPPC and PG are preferred component(s) advantageously utilized in thepresent inventions methods for administering therapeutically activeagents to the middle ear and auditory tube. In addition, these lipidsincrease the pressure equalizing performance of the auditory tube bydirect result of their surfactant qualities. DPPC may be selected to bepresent in the composition over a fairly wide range. Percentages of DPPCmay be s as low as 70% and as high as 99.5% of the lipids by weight withlittle change in the in-vitro properties, and the effectiveness of thepresent method. However, 99.5% DPPC by weight is selected for thepreferred embodiment.

Throughout this specification and in the claims, the phrase “increasingpressure equalization performance of the auditory tube” and “increasingthe pressure equalization performance of the eustachian tube” both referto the increased ease and ability of a mammal upon which the presentmethod is practiced, to utilize the pathway provided by the lumen of theeustachian tube to equalize the pressure of the middle ear with ambientpressure surrounding the mammal. The increased ease and ability is theresult of the decrease in opening pressure of the lumen of the mammalianeustachian tube provided by the present invention.

Another lipid that can be utilized in practicing the methods of thepresent invention is cholesteryl palmitate( CP), which also serves as aspreading agent. This cholesteryl ester is a neutral lipid which belongsto a class of organic compounds that are also cell constituents and areextractable by non-polar solvents such as chloroform, methanol, ether,etc. The structural formula of CP is:

CP may be obtained commercially in a highly purified form from FlukaChemical Co. and Sigma Chemical Co. The CP component constitutes a minorportion of the composition, since it is selected to be present in anamount ranging from 0.5% to 10% by weight. Also, the preferred ratio ofDPPC to CP is 99.5 DPPC to 0.5 CP by weight. However, the percentagesmay be altered within that range without undue interference in desiredproperties needed for drug delivery and surfactant activity.

The term “therapeutically active agent” and “therapeutically activeagent effective in the treatment of otitis media,” as utilized in andthroughout this specification and claims, refers to those drugseffective in treatment of otitis media including, but not limited toanti-inflammatory agents including, for example, betamethasone,including, for example, betamethasone dipropionate and betamethasonevalerate as well as all other effective formulations; de-congestiveagents such as phenylephrine, including, for example, phenylephrine HCLand phenylephrine bitartrate and all other effective formulationsthereof; and antibiotics including, for example erythromycin,amoxicillin, zythromax, and augmentin (amoxicillin and clavuliic acid)in all of their effective formulations. The term “all of their effectiveformulations” as used throughout this specification and in the claimsrefers to those specific species of a particular therapeutic agenteffective in the treatment of otitis media.

The combination of lipid component(s) and spreading agent component(s)disclosed herein, may be referred to, collectively, as the “carrier”when said combination is mixed with a therapeutically active agent so asto act as a carrier therefore. When practicing the method of the presentinvention wherein therapeutically active agents are administereddirectly to mammalian eustachian tube and middle ear tissues, it ispreferred that carrier, the mixture of one or more lipids and one ormore spreading agents, be comprised of a mixture of DPPC and CP in a200:1 ratio (by weight). However, it has been found that a ratio rangeof from 5:1 to 300:1 (DPPC/CP) will also produce an effective carrierfor this embodiment. If, for example, the therapeutic agent is selectedto be betamethasone, the weight ratio of betamethasone to carrier(DPPC/CP) is advantageously selected to be 1 microgram betamethasone to5 milligrams carrier. However, it has been found that a weight ratiorange of 0.5 to 1000 micrograms betamethasone/5 milligrams carrieryields an effective and functional mixture.

When practicing the method of the present invention wherein thetherapeutically active agent is selected to be phenylephrine it ispreferred to select the weight ratio of phenylephrine to carrier to be160 micrograms/995 milligrams. However, it has also been found that aweight ratio range of from 50 to 5000 micrograms (phenylephrine): 995 to900 milligrams carrier, respectively, forms an effective mixture andfunctional mixture. The term “effective and functional mixture” asutilized throughout this application and in the claims refers to theeffectiveness of the mixture of lipid crystals in combination with saidtherapeutically active agent resulting from the combinations disclosedherein in: (a) reaching the target tissue of the eustachian tube andmiddle ear; (b) reducing the surface tension thereupon; and (c)delivering a uniform dose of therapeutic agent directly to and spreadinguniformly upon said tissues so as to effectively bring symptomaticrelief and/or resolution of the afore-mentioned pathological conditionsincluding otitis media.

When practicing the method of the present invention wherein thetherapeutically active agent is selected to be the antibioticerythromycin, the ratio of erythromycin to carrier is advantageouslyselected to be 200 mg antibiotic to 800 mg carrier (DPPC/CP) by weight.However, a weight range of from 50 to 200 mg erythromycin: from 950 to800 mg carrier, respectively, has been found to be fully effective inpracticing the present method.

The fluorocarbon propellants utilized in practicing the method of thepresent invention, namely: trichlorodifluoromethane,dichlorodifluoromethane, and tetrafluoromethane or mixtures thereof,which are commercially available from Union Carbide Corp., Danbury,Conn. and Armstrong Laboratories, West Roxbury Mass. are advantageouslyselected for formation of the lipid crystalline figures of the presentinvention. The fluorocarbon propellants are present over a range of 2 to30 times the amount, by weight, of lipid, but components of lipid andfluorocarbon propellants both are needed in order to obtain the requiredlipid crystalline figures.

In practicing the methods of the present invention whereintherapeutically effective agents are administered directly to the middleear for the treatment of otitis media, DPPC is advantageously selectedas the major lipid component since the amphoteric nature of thisphospholipid allows the molecule to act as a carrier for any drug ortherapeutic agent. However, the presence of a charge on other lipidcomponents (a negative charge on PG, for example) would alter andfurther improve the carrying capacity of the lipid crystals for aparticular therapeutic agent.

In addition to erythromycin and amoxicillin, the method of the presentinvention also contemplates selecting zythromax and Augmentin(amoxicillin+clavulinic acid) as antibiotic therapeutic agents. However,because of the highly amphoteric nature of the carrier utilized herein,the use of any presently known and available, as well as antibioticdeveloped in the future capable of providing effective treatment ofinfections of the middle ear and eustachian tube are contemplated andfully functional with the methods and compositions herein.

EXAMPLE 1

The aerosolized drug delivery system of the present invention wasprepared from chromatographically pure (greater than 99%) DPPC and CP.Both materials were purchased from suppliers on the commercial marketwhere they are available from several chemical supply houses.Specifically, the DPPC and CP were purchased from Sigma Chem., St Louis,Mo. All purchased materials were checked for purity by standardchromatographic analysis. The betamethasone utilized in this example wasalso purchased from Sigma Chemical. The DPPC and CP were then mixed inthe dry powder form in a weight ratio of 200:1 (DPPC:CP). To 5milligrams of the resultant carrier, 1 microgram of betamethasone wasadded in order to yield a weight ratio of 5000:1 (carrier:betamethasone). Then 5 grams of this mixture was suspended in 55 gramsof the first propellant, trichloromonofluoromethane (P11) and subdividedinto 30 ml. Wheaton plastic-coated glass bottles with a 20 mm neckfinish. Valois metered dose valves were then crimped onto each bottlethrough which 40 gms of the second propellant, dichlorodifluoromethane(P12), was passed. The filled bottles were then gently shaken todisperse the solids that are insoluble in the propellants. The bottleswere thereafter immersed in a water bath to test for leaks and thenfitted with a nasal administration adapter. The suspension washomogenous. After standing at room temperature for about three days, apellicle forms on top of the propellants but is easily re-suspended bygentle shaking. The size of the metering valve can be varied to deliverfrom 1 mg up to 5.4 mg of the DPPC:CP:Betamethasone aerosolized mixture.However, metered dose valves having a greater dosing range are alsocontemplated and can be utilized in other embodiments of the presentinvention.

EXAMPLE II

The aerosolized drug delivery system of the present invention wasprepared from chromatographically pure (greater than 99%) DPPC and CP.Both materials were purchased from suppliers on the commercial marketwhere they are available from several chemical supply houses.Specifically, the DPPC and CP were purchased from Sigma Chem., St Louis,Mo. The phenylephrine utilized in this example can also be purchasedfrom Sigma Chem., St Louis, Mo. All purchased materials were checked forpurity by standard chromatographic analysis. The DPPC and CP were thenmixed in the dry powder form in a weight ratio of 200:1 (DPPC:CP).Thereafter, to 995 milligrams of the resultant carrier, 160 microgramsof phenylephrine was added so as to yield an approximate 6200:1 weightratio of carrier to phenylephrine. Then 5 grams of the resultant mixture(DPPC/CP/phenylephrine) was suspended in 55 grams of the firstpropellant, trichloromonofluoromethane (P11) and subdivided into 30 ml.Wheaton plastic-coated glass bottles with a 20 mm neck finish. Valoismetered dose valves were then crimped onto each bottle through which 40gms of the second propellant, dichlorodifluoromethane (P12), was passed.The filled bottles were then gently shaken to disperse the solids thatare insoluble in the propellants and nasal administration adaptors. Thebottles were immersed in a water bath to test for leaks and then fittedwith a nasal administration adapter. The suspension was homogenous.After standing at room temperature for about three days, a pellicleforms on top of the propellants but is easily re-suspended by gentleshaking. The size of the metering valve can be varied to deliver from 1mg up to 5.4 mg of the DPPC:CP: phenylephrine aerosolized mixture.However, metered dose valves having a greater dosing range are alsocontemplated and can be advantageously utilized in practicing themethods of the present invention.

EXAMPLE III

The aerosolized drug delivery system of the present invention wasprepared from chromatographically pure (greater than 99%) DPPC and CP.Both materials were purchased from suppliers on the commercial marketwhere they are available from several chemical supply houses.Specifically, the DPPC and CP were purchased from Sigma Chem., St Louis,Mo. The erythromycin utilized in this example can also be purchased fromSigma Chem., St Louis, Mo. All purchased materials were checked forpurity by standard chromatographic analysis. The DPPC and CP were thenmixed in the dry powder form in a weight ratio of 200:1 (DPPC:CP).Thereafter, to 800 milligrams of the resultant carrier, 200 milligramsof erythromycin was added so as to yield an approximate 4:1 weight ratioof carrier to erythromycin. Then 5 grams of the resultant mixture(DPPC/CP/erythromycin) was suspended in 55 grams of the firstpropellant, trichloromonofluoromethane (P11) and subdivided into 30 ml.Wheaton plastic-coated glass bottles with a 20 mm neck finish. Valoismetered dose valves were then crimped onto each bottle through which 40gms of the second propellant, dichlorodifluoromethane (P12), was passed.The filled bottles were then gently shaken to disperse the solids thatare insoluble in the propellants. The bottles were immersed in a waterbath to test for leaks and then fitted with a nasal administrationadapter. The suspension was homogenous. After standing at roomtemperature for about three days, a pellicle forms on top of thepropellants but is easily re-suspended by gentle shaking. The size ofthe metering valve can be varied to deliver from 1 mg up to 5.4 mg ofthe DPPC:CP: erythromycin aerosolized mixture. However, metered dosevalves having a greater dosing range are are also contemplated and canbe advantageously utilized in practicing the methods of the presentinvention.

EXAMPLE IV

The aerosolized drug delivery system of the present invention wasprepared from chromatographically pure (greater than 99%) DPPC, PG andCP. All of these materials were purchased from suppliers on thecommercial market where they are available from several chemical supplyhouses. Specifically, the DPPC, CP and PG were purchased from SigmaChem., St Louis, Mo. The erythromycin utilized in this example can alsobe purchased from Sigma Chem. All purchased materials were checked forpurity by standard chromatographic analysis. The DPPC, PG and CP werethen mixed in the dry powder form in a weight ratio of 7:1:0.35(DPPC:PG:CP). Thereafter, to 800 milligrams of the resultant carrier,200 milligrams of erythromycin was added so as to yield an approximate4:1 weight ratio of carrier to erythromycin. Then 5 grams of thismixture was suspended in 55 grams of the first propellant,trichloromonofluoromethane (P11) and subdivided into 30 ml. Wheatonplastic-coated glass bottles with a 20 mm neck finish. Valois meteringvalves were crimped onto each bottle through which 40 gms of the secondpropellant, dichlorodifluoromethane (P12), was passed. The filledbottles were then gently shaken to disperse the solids that areinsoluble in the propellants. The bottles were thereafter immersed in awater bath to test for leaks and then fitted with a nasal administrationadapter. The suspension was homogenous. After standing at roomtemperature for about three days, a pellicle forms on top of thepropellants but was easily resuspended by gentle shaking. The size ofthe metering valve can be varied to deliver from 1 mg up to 5.4 mg ofthe DPPC:PG:CP: erythromycin aerosolized mixture.

EXAMPLE V

Chromatographically pure DPPC and CP (99% pure) were obtained fromAvanti Polar Lipids Co. of Birmingham, Ala. and Sigma Chemical Co. ofSt. Louis, Mo.

DPPC and CP were mixed in a weight ratio of 200:1 (DPPC:CP). Then 5grams of this mixture was suspended in 55 grams of the first propellant,trichloromonofluoromethane (P11) and subdivided into 30 ml. Wheatonplastic-coated glass bottles with a 20 mm neck finish. Valois meteringvalves were crimped onto each bottle through which 40 gms of the secondpropellant, dichlorodifluoromethane (P12), was passed. The filledbottles were then gently shaken to disperse the solids that areinsoluble in the propellants. The bottles were thereafter immersed in awater bath to test for leaks and then fitted with a nasal inhalationadapter. The suspension was homogenous. After standing at roomtemperature for about three days, a pellicle forms on top of thepropellants but was easily re-suspended by gentle shaking. The size ofthe metering valve can be varied to deliver from 1 mg up to 5.4 mg ofthe DPPC:CP aerosolized mixture.

The afore-described Examples “I” through “IV” are specific embodimentsof the aerosolized drug delivery system utilized in practicing themethod of the present invention. Each of the afore-mentioned Examples“I” through “IV” are administered by releasing a metered dose of themixtures, by means of a nasal administration adaptor, through the nose.The aerosolized mixture, propelled by the above-described propellants,is then deposited about the anterior terminus of the eustachian tube atits communication with the nasopharynx. Thereafter, the crystallinelipid figures come in contact with mammalian auditory tube tissue and,forms an amorphous spread film layer upon the air/liquid interfaceresident upon the epithelial lined lumen. The spread film, in turn,uniformly spreads both the surfactant and the therapeutic agent carriedthereby throughout the lumen of the tube and into the tissues of boththe auditory tube and middle ear.

In the above-described Example “I”, wherein the therapeutically activeagent is the anti-inflammatory, betamethasone, the agent acts directlyupon the auditory tube itself, reducing the excess mucoid secretions andswelling of the auditory tube characteristic of OME. Both excess mucoidsecretions and inflammatory swelling of the tube substantially increaseauditory tube opening pressure, or, in other words, both mucoidsecretions and tissue swelling tend to increase the force required toopen the lumen and form a patent duct between the middle ear andnasopharynx. However, DPPC and/or DPPC/PG lipids act independently ofselected therapeutic agent(s) to reduce the surface tension of the lumenby reducing the intermolecular and surface charges found at theair/interface of the secretion covered lumen.

The present invention also contemplates the use of antibiotics such as,for example, erythromycin (Example “III” and “IV”), amoxicillin,zythromax and augmentin (amoxicillin+clavulinic acid). In suchembodiments, the DPPC and/or DPPC/PG act to introduce such drugs to theauditory tube and middle ear in the same manner as described immediatelyabove in regards to anti-inflammatory agents. However, while DPPC andDPPC/PG aerosolized mixtures act as carriers for such drugs, they alsocontinue to provide the decrease in surface tension and opening pressureof the eustachian tube. Therefore, in instances in which the method ofthe present invention is utilized to treat a bacterial infection of themiddle ear, direct application of antibiotic therapy to the tympaniccavity/eustachian tube bacterial source, and increased patency of theauditory tube is provided.

In Example “V”, above, preparation of an aerosolized mixture of lipidcrystals for use in practicing the method of the present invention isdisclosed that is advantageously formulated for enhancing pressureequalization performance of mammalian eustachian tubes without the useof a therapeutically active agent. In practicing the second preferredembodiment of the present invention, the aerosolized mixture, propelledby the above-described propellants, is deposited about the anteriorterminus of the eustachian tube at its communication with thenasopharynx. Thereafter, the crystalline lipid figures come in contactwith auditory tube and form an amorphous spread film layer upon theair/liquid interface of the epithelial lined lumen which, in turn,uniformly spreads the lipid mixture throughout the lumen of the tube andinto the middle ear. At the same time, surface tension of an air/liquidinterface located upon the eustachian tube's epithelial lined lumen isreduced to provide said increased performance. In this example, a methodof enhancing pressure equalization performance of mammalian eustachiantubes is disclosed wherein surface tension of an air/liquid interfacelocated upon the eustachian tube's epithelial lined lumen is reduced toprovide said increased performance. However no therapeutically activeagent is included in the aerosolized mixture or contemplated in thisembodiment. Increased auditory tube patency is provided by means ofinteraction of the surfactant/spreading agent combination alone.However, in many instances, especially in the absence of infectionand/or inflammatory disease, use of anti-inflammatory and antibioticsmay not be necessary. As stated above, a principal cause of OME isthought to be reduced eustachian tube patency. Since OME, as opposed toacute otitis media, occurs in the absence of infection, use ofantibiotics would be of little to no value in the treatment of suchpathology. In addition, for those embodiments and applications of thepresent invention specifically directed at enhancing performance of theauditory tube for individuals who experience equilibration difficulties(solely in connection with flying or diving), elimination of unnecessarydrugs would be highly desirable.

EFFECT OF AEROSOLIZED LIPID CRYSTALS ON PASSIVE OPENING PRESSURE OF THEEUSTACHIAN TUBE IN AN ANIMAL MODEL

The aerosolized lipid crystal mixture described in “Example V”, above,was administered, through the nose, to Mongolian Gerbils and WistarMice. Administration of the mixture resulted in a reduction, from aninitial opening pressure of 36.82+/−2.03 mmHG to 29.16+/−2.67 in theMongolian Gerbils and from an initial opening pressure of 43.1+/−1.43mmHG to 32.1+/−2.21. Therefore, the composition and method of thepresent invention effectively increased eustachian tube patency by meansof an exogenous nasally administered surfactant.

EFFECT OF AEROSOLIZED LIPID CRYSTALS WITH AND WITHOUT THERAPEUTICALLYACTIVE AGENT UPON OME

Otitis media with effusion (OME) was developed in 75 gerbils by intratympanic injection of 100-ug/mL solution of lipopolysaccharide derivedfrom Klebsiella pneumoniae. The animals were grouped and the followingdrugs were sprayed intra nasally, prepared in an aerosolized metereddose inhaler (MDI) viz 1) Placebo (normal saline); 2) Surfactant alone(DPPC:CP (200:1); 3) Surfactant with betamethasone (5 mg carrier to 10micrograms betamethasone diproprionate); 4) Surfactant withphenylephrine (995 mg carrier to 160 micrograms phenylephrine HCl).In-vivo Typanometry and Micro-otoscopy was done on the 3^(rd), 5^(th),7^(th), 7^(th), 10^(th), 12^(th), 15^(th), 16^(th), 22^(nd) and 30^(th)days after the development of OME. Resolution of OME was observed bymicro-otoscopy on the 6^(th), day in the surfactant with betamethasonegroup, on the 10^(th) day with the surfactant alone group, and on the16^(th) day for all other groups. The experimental results demonstratethe effectiveness of those methods of the present infection utilizinganti-inflammatory agents, as well as those utilizing the disclosedaerosolized lipid crystals alone, in providing effective treatment ofotitis media.

STRUCTURAL CHARACTERISTICS

Particle Size and Gross Configuration

Particle size of the nebulized crystals produced and utilized inpracticing the present invention is, as discussed below, critical toeffective administration. The size (diameter) of the lipid crystals weretherefore determined utilizing in a cascade impactor. Flow through theimpactor was adjusted to be substantially identical to the flow from anebulizer utilized in practicing the disclosed method. All of the lipidcrystals were found to have a diameter equal to or less than 16 microns.The diameter of about 95 percent of the particles were found to be equalto or less than 4 microns in diameter. Of the particles found to be 4microns or less, half were, in fact, 1 micron in diameter. The meandiameter demonstrated by the lipid crystals utilized in the method ofthe present invention was 1.75+/−25 microns.

Micronization may be advantageously utilized in order to insure reducedparticle size. Therefore, the methods of the present invention alsocontemplate the use of a micronization mill such as, for example, the“DYNO” mill, type KDL, manufactured by Glen Mills Inc., of New Jersey inthe preparation of the aerosolized mixture. For example, approximately83 grams of CP and 13.33 g of DPPC powder were weighed and transferredto a bead mill within the milling chamber of a DYNO mill (having about480 cc of glass beads). The chamber was then sealed. Thereafter, 1 literof HFC-134a was added and the system chilled to about −10° C. at apressure of approximately 65 psi. Milling was achieved in about 1 hour.Thereafter, the resultant slurry was utilized to fill 15 mil epoxyphenolic lined aluminum cans (Safet Embamet, St. Florantine, France),fitted with Valois metering valves (DFI/ACT/kematal, Valois, Le Neuborg,France with Micron-4 acuators (also Valois). A laser particle sizer,model 2600c, Malvern Instruments, Inc., was thereafter utilized to sizethe resultant particles as shown in Table “1”, below. This dataindicates that approximately 90% of the particles emitted fro the valveand actuator system are under 7 μm or less in diameter. The meandiameter (arithmetic mean) is approximately 5 μm and the mass medianaerodynamic diameter (MMAD) is about 3.4 μm with a geometric standarddeviation (GSD) of about 0.5. Particle size results in physicallyunstable dispersions should change dramatically over a few days ofundisturbed storage.

TABLE 1 Day Particle Size Summary Number 90 Percentile 50 Percentile % ≦10 μm MMAD GSD 1 6.9 μm 5.1 μm 100 3.4 0.5 2 6.8 μm 4.8 μm 99.9 3.5 0.53 7.3 μm 5.4 μm 100.0 3.5 0.5 4 6.5 μm 4.6 μm 99.9 3.2 0.5 5 6.8 μm 4.7μm 100.0 3.4 0.5 Mean 6.9 ± 0.3 μm 4.9 ± 0.3 μm 100.0 3.4 ± 0.1 0.5

Structural characteristics of the mixture of lipid crystals utilized inpracticing the present invention were further assessed by capturing theaerosolized particles on standard scanning electron microscopic gridsfixed to glass slides at 220° C., (dry). The lipids deposited on glassboth as dry particles and as coalesced droplets. The elaster evaporatedimmediately leaving dry lipid. The dry lipids, were fixed in osmiumvapor (O₅O₄), coated and viewed with a scanning electron microscope.Crystalline figures about 100 angstroms thick, were grouped in clumps onthe dry surface. This is a unique configuration.

Crystalline Structure

The mixture of one or more lipids, one or more spreading and one or morefluorocarbon propellants disclosed in the present invention isespecially formulated and combined to form a unique crystallinestructure with physical dimensions highly advantageous to allembodiments. For example, the crystalline structure results in, asdiscussed above, a mean particle size of 1.75 microns. The minutephysical dimensions of the individual nebulized particles enables thepropellant utilized in practicing the present invention to easily andeffectively transfer the disclosed mixture to and throughout the desiredtarget tissue. A larger physical configurations such as, for example, aliposome, would not enable such diminutive particle size within andeffective physical transport by the propellant.

FUNCTIONAL PROPERTIES

The aerosolized mixture of the present invention is crystalline. Thecrystalline nature of the mixture imparts increased efficiency ofparticle dispersion within the aerosol mist applied by means of ametered-dose nebulizer. Upon application, the fluorocarbon medium,either chlorofluorocarbon or hydrofluorocarbon, vaporizes rapidly andthe DPPC/CP, DPPC/CP drug, DPPC/PG drug or DPPC/PG/CP drug dispersiondeposits on an aqueous surface at 37° C., initially in the crystallineform, and then, instantaneously, spreads over the surface as anamorphous surface film. In embodiments wherein a therapeutic is combinedwith the carrier, the drug likewise is spread, uniformly, upon theaqueous surface.

The surfactant/spreading agent functions and characteristics of themethod and composition of the present invention were tested as follows.Aerosolized crystalline figures of the present invention were impactedupon a liquid surface (normal saline solution, NSS) at 37° C., 100%humidity in a surface balance resulted in a rapid spreading of aprincipally amorphous film that covered the entire surface (18.1 cm²).Surface tension of the film was measured during expansion andcompression at 370 C., 100% humidity. Film expansion to 110.4 cm²produced a surface tension of 72 dynes/cm and compression to 18.1 cm²lowered surface tension to less than 1 dyne/cm.

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and notlimitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the following claims.

I claim:
 1. A method of treating otitis media comprising administering adose of a mixture of lipid crystals, as an aerosol, through an externalnasal airway of a mammal, said mixture being comprised of: one or morelipid surfactant, one or more spreading agent and at least onepropellant in which said surfactants and spreading agents are notsoluble, said surfactants and spreading agents being selected from thegroup consisting of cholesteryl esters, phospholipids, carbohydrates,and proteins, all in powder form and said surfactants being present inan amount of from about 80 to about 95.5 weight percent and saidspreading agents being present in an amount of from about 20 to about0.5 weight percent based upon total weight of said lipid surfactants andspreading agents in said mixture, wherein when said propellants areevaporated therefrom, said aerosolized mixture of lipid crystals isprovided.
 2. The method of claim 1 wherein a metered dose inhalationdevice is utilized to administer said mixture through an external nasalorifice of said mammal.
 3. The method of claim 1 wherein the lipids areselected from the group consisting of phospholipids, neutral lipids andmixtures thereof.
 4. The method of claim 3 wherein the phospholipids areany of a class known as phosphatidylcholines.
 5. The method of claim 4wherein the phosphatidylcholine is any fully saturated diacylphosphatidylcholine.
 6. The method of claim 5 wherein the fullysaturated diacylphosphatidylcholine is 1,2 dipalmitoylphosphatidylcholine.
 7. The method of claim 3 wherein the phospholipidis diacylphosphatidylglycerol.
 8. The method of claim 3 wherein thephospholipid is diacylphosphatidylethanolamine.
 9. The method of claim 3wherein the phospholipid is diacylphosphatidylserine.
 10. The method ofclaim 3 wherein the phospholipid is diacylphosphatidylinositol.
 11. Themethod of claim 3 wherein the phospholipid is a sphingomyelin.
 12. Themethod of claim 3 wherein the phospholipid is Cardiolipin.
 13. Themethod of claim 3 wherein the phospholipid is a lysophospholipid. 14.The method of claim 3 wherein the phospholipid is plasmalogen.
 15. Themethod of claim 3 wherein the phospholipid is a diether phosphonolipid.16. The method of claim 3 wherein the phospholipid is adialkylphospholipid.
 17. The method of claim 1 wherein the carbohydratesare selected from the group consisting of glucose, fructose, galactose,pneumogalactan and dextrose.
 18. The method of claim 1 wherein theprotein is selected from the group consisting of albumin and pulmonarysurfactant specific proteins A and B and C and D, their syntheticanalogs and mixtures thereof.
 19. The method of claim 1 wherein thecholesteryl ester is selected from the group consisting of cholesterylpalmitate, cholesteryl oleate and cholesteryl stearate.
 20. The methodof claim 1 wherein the propellant is a fluorocarbon propellant.
 21. Themethod of claim 19 wherein said fluorocarbon propellant is selected fromthe group consisting of a chlorofluorocarbon, hydrofluorocarbon andmixtures thereof.
 22. The method of claim 1 wherein said propellant iscarbon dioxide.
 23. The method of claim 1 wherein 95 percent of saidlipid crystals demonstrate a particle size no greater than 4 microns indiameter.
 24. A method of treating otitis media comprising administeringa dose of a mixture of lipid crystals in combination with at least onetherapeutically active agent effective in the treatment of otitis media,as an aerosol, through an external nasal airway of a mammal, saidmixture being comprised of: one or more lipid surfactant, one or morespreading agent, one or more therapeutically active agent and at leastone propellant in which said surfactants, spreading agents andtherapeutic agent are not soluble, said surfactants and spreading agentsbeing selected from the group consisting of cholesteryl esters,phospholipids, carbohydrates, and proteins, all in powder form and saidsurfactants being present in an amount of from about 80 to about 95.5percent by weight and said spreading agents being present in an amountof from about 20 to about 0.5 weight percent based upon total weight ofsaid lipid surfactants and spreading agents in said mixture wherein whensaid propellants are evaporated therefrom, said aerosolized mixture oflipid crystals in combination with at least one therapeutically activeagent is provided.
 25. The method of claim 24 wherein a metered doseinhalation device is utilized to administer said mixture of lipidcrystals in combination with said therapeutically active agent.
 26. Themethod of claim 24 wherein the lipids are selected from the groupconsisting of phospholipids, neutral lipids and mixtures thereof. 27.The method of claim 26 wherein the phospholipids are any of a classknown as phosphatidylcholines.
 28. The method of claim 27 wherein thephosphatidylcholine is any fully saturated diacyl phosphatidylcholine.29. The method of claim 28 wherein the fully saturated diacylphosphatidylcholine is 1,2, dipalmitoyl phosphatidylcholine.
 30. Themethod of claim 26 wherein the phospholipid isdiacylphosphatidylglycerol.
 31. The method of claim 26 wherein thephospholipid is diacylphosphatidylethanolamine.
 32. The method of claim26 wherein the phospholipid is diacylphosphatidylserine.
 33. The methodof claim 26 wherein the phospholipid is diacylphosphatidylinositol. 34.The method of claim 26 wherein the phospholipid is a sphingomyelin. 35.The method of claim 26 wherein the phospholipid is Cardiolipin.
 36. Themethod of claim 26 wherein the phospholipid is a lysophospholipid. 37.The method of claim 26 wherein the phospholipid is plasmalogen.
 38. Themethod of claim 26 wherein the phospholipid is a diether phosphonolipid.39. The method of claim 26 wherein the phospholipid is adialkylphospholipid.
 40. The method of claim 24 wherein thecarbohydrates are selected from the group consisting of glucose,fructose, galactose, pneumogalactan and dextrose.
 41. The method ofclaim 24 wherein the protein is selected from the group consisting ofalbumin and pulmonary surfactant specific proteins A and B and C and D,their synthetic analogs and mixtures thereof.
 42. The method of claim 24wherein the cholesteryl ester is selected from the group consisting ofcholesteryl palmitate, cholesteryl oleate and cholesteryl stearate. 43.The method of claim 24 wherein said therapeutically active agent is ananti-inflammatory agent.
 44. The method of claim 43 wherein saidanti-inflammatory agent is betamethasone.
 45. The method of claim 44wherein said betamethasone is selected from the group consisting ofbetamethasone dipropionate, betamethasone valerate and mixtures thereof.46. The method of claim 24 wherein said therapeutically active agent isantibiotic.
 47. The method of claim 46 wherein said antibiotic isselected from the group consisting of erythromycin, amoxicillin,azithromycin clavulanic acid and mixtures thereof.
 48. The method ofclaim 24 wherein said therapeutically active agent is a decongestant.49. The method of claim 48 wherein said decongestant is phenylephrine.50. The method of claim 49 wherein said phenylephrine is selected fromthe group consisting of phenylephrine HCl, phenylephrine bitartrate andmixtures thereof.
 51. The method of claim 24 wherein the propellant is afluorocarbon.
 52. The method of claim 51 wherein the fluorocarbonpropellant is selected from the group consisting of achlorofluorocarbon, hydrofluorocarbon and mixtures thereof.
 53. Themethod of claim 24 wherein the propellant is carbon dioxide.
 54. Themethod of claim 24 wherein 95 percent of said lipid crystals demonstratea particle size no greater than 4 microns in diameter.
 55. A process forpreparing a eustachian tube lumen patency enhancing medicamentcomprising: combining one or more lipid surfactants, one or morespreading agents and one or more propellants to form a mixture, saidlipids and said spreading, agents being selected from the groupconsisting of cholesteryl esters, phospholipids, carbohydrates, andproteins, all in powder form, said lipids and said spreading agentsbeing insoluble in the propellants, said lipid surfactants beingselected to be present in an amount of from about 80 to about 99.5weight percent and said spreading agents are selected to be present inan amount of from about 20 to about 0.5 weight percent, based upon totalweight of said lipid surfactants and spreading agents in said mixture,wherein when said propellants are evaporated therefrom, a mixture ofaerosolized lipid crystals is released for se as the medicament.
 56. Theprocess of claim 55 wherein said mixture is bottled in a metered dosedevice.
 57. The process of claim 55 wherein the lipids are selected fromthe group consisting of phospholipids, neutral lipids and mixturesthereof.
 58. The process of claim 57 wherein the phospholipids are anyof a class known as phosphatidylcholines.
 59. The process of claim 58wherein the phosphatidylcholine is any fully saturated diacylphosphatidylcholine.
 60. The process of claim 59 wherein said fullysaturated diacyl phosphatidylcholine is 1,2, dipalmitoylphosphatidylcholine.
 61. The process of claim 57 wherein thephospholipid is diacylphosphatidylglycerol.
 62. The process of claim 57wherein the phospholipid is diacylphosphatidylethanolamine.
 63. Theprocess of claim 52 wherein the phospholipid isdiacylphosphatidylserine.
 64. The process of claim 57 wherein thephospholipid is diacylphosphatidylinositol.
 65. The process of claim 57wherein the phospholipid is a sphingomyelin.
 66. The process of claim 57wherein the phospholipid is Cardiolipin.
 67. The process of claim 57wherein the phospholipid is a lysophospholipid.
 68. The process of claim57 wherein the phospholipid is plasmalogen.
 69. The process of claim 57wherein the phospholipid is a diether phosphonolipid.
 70. The process ofclaim 57 wherein the phospholipid is a dialkylphospholipid.
 71. Theprocess of claim 55 wherein the carbohydrates are selected from thegroup consisting of glucose, fructose, galactose, pneumogalactan anddextrose.
 72. The process of claim 55 wherein the protein is selectedfrom the group consisting of albumin and pulmonary surfactant specificproteins A and B and C and D, their synthetic analogs and mixturesthereof.
 73. The process of claim 55 wherein the cholesteryl ester isselected from the group consisting of cholesteryl palmitate, cholesteryloleate and cholesteryl stearate.
 74. The process of claim 55 wherein thepropellant is a fluorocarbon.
 75. The process of claim 74 wherein thefluorocarbon propellant is selected from the group consisting of achlorofluorocarbon, hydrofluorocarbon and mixtures thereof.
 76. Theprocess of claim 55 wherein the propellant is carbon dioxide.
 77. Theprocess of claim 55 wherein 95 percent of said lipid crystalsdemonstrate a particle size no greater than 4 microns in diameter.
 78. Aprocess for preparing an otitis media medicament comprising: combiningone or more lipid surfactants, one or more spreading agents, one or moretherapeutically active agent effective in the treatment of otitis mediaand one or more propellant to form a mixture, said lipids and saidspreading agents being selected from the group consisting of cholesterylesters, phospholipids, carbohydrates, and proteins, all in powder form,wherein said lipids, said spreading agents and said therapeuticallyactive agents are insoluble in the propellants, said lipid surfactantsare selected to be present in an amount of from about 80 to about 99.5weight percent and said spreading agents are selected to be present inan amount of from about 20 to about 0.5 weight percent, based upon totalweight of said lipid surfactants and spreading agents in said mixture;and wherein when said propellants are evaporated therefrom, a mixture ofaerosolized lipid crystals is released for use as the medicament. 79.The process of claim 78 wherein said mixture is bottled in a metereddose device.
 80. The process of claim 78 wherein the lipids are selectedfrom the group consisting of phospholipids, neutral and mixturesthereof.
 81. The process of claim 80 wherein the phospholipids are anyof a class known as phosphatidylcholines.
 82. The process of claim 81wherein the phosphatidylcholine is any fully saturated diacylphosphatidylcholine.
 83. The process of claim 82 wherein the fullysaturated diacyl phosphatidylcholine is 1,2 dipalmitoylphosphatidylcholine.
 84. The process of claim 80 wherein thephospholipid is diacylphosphatidylglycerol.
 85. The process of claim 80wherein the phospholipid is diacylphosphatidylethanolamine.
 86. Theprocess of claim 80 wherein the phospholipid isdiacylphosphatidylserine.
 87. The process of claim 80 wherein tithephospholipid is diacylphosphatidylinositol.
 88. The process of claim 80wherein the phospholipid is a sphingomyelin.
 89. The process of claim 80wherein the phospholipid is Cardiolipin.
 90. The process of claim 80wherein the phospholipid is a lysophospholipid.
 91. The process of claim80 wherein the phospholipid is plasmalogen.
 92. The process of claim 80wherein the phospholipid is a diether phosphonolipid.
 93. The process ofclaim 80 wherein the phospholipid is a dialkylphospholipid.
 94. Theprocess of claim 78 wherein the carbohydrates are selected from thegroup consisting of glucose, fructose, galactose, pneumogalactan anddextrose.
 95. The process of claim 78 wherein the protein is selectedfrom the group consisting of albumin and pulmonary surfactant specificproteins A and B and C and D, their synthetic analogs and mixturesthereof.
 96. The process of claim 78 wherein the cholesteryl ester isselected from the group consisting of cholesteryl palmitate, cholesteryloleate and cholesteryl stearate.
 97. The process of claim 78 whereinsaid therapeutically active agent is an anti-inflammatory agent.
 98. Theprocess of claim 97 wherein said anti-inflammatory agent isbetamethasone.
 99. The process of claim 98 wherein said betamethasone isselected from the group consisting of betamethasone dipropionate,betamethasone valerate and mixtures thereof.
 100. The process of claim78 wherein said therapeutically active agent is an antibiotic.
 101. Theprocess of claim 100 wherein said antibioitic is selected from the croupconsisting of erythromycin, amoxicillin, azithromycin, clavulanic acid,and mixtures thereof.
 102. The process of claim 78 wherein saidtherapeutically active agent is a decongestant.
 103. The process ofclaim 102 wherein said decongestant is phenylephrine.
 104. The processof claim 103 wherein said phenylephrine is selected from the groupconsisting of phenylephrine HCl, phenylephrine bitartrate and mixturesthereof.
 105. The process of claim 78 wherein the propellant is afluorocarbon.
 106. The process of claim 105 wherein the fluorocarbonpropellant is selected from the group consisting of achlorofluorocarbons hydrofluorocarbon and mixtures thereof.
 107. Theprocess of claim 78 wherein the propellant is carbon dioxide.
 108. Theprocess of claim 78 wherein 95 percent of said lipid crystalsdemonstrate a particle size no greater than 4 microns in diameter.